Any number of insults, such as infections, vascular disorders, or sounds of sufficient intensity and duration will damage the ear and result in temporary or permanent hearing loss. The hearing loss may range from mild to profound, and may also be associated with conditions such as tinnitus, which is the perception of a ringing, roaring, buzzing, or clicking sound etc that occurs inside the head when no external sound is present. Repeated sound overstimulation or other insults cumulative over a lifetime and can cause permanent damage that is not currently treatable. Hearing impairment has a major impact on one's communication ability and even mild impairment may adversely affect the quality of life for millions. Unfortunately, although such hearing loss is preventable, our increasingly noisy environment places more and more people at risk.
L-glutamate (glutamate) is the most important afferent neurotransmitter in the auditory system, and is used by the sensory inner hair cells (IHC) of the cochlea to transduce the mechanical displacement of the basilar membrane into activity of the primary auditory afferent nerve fibers (for a review, see, e.g., Puel (1995) Neurobiol 47:449-476). The ionotropic receptors with which glutamate interacts during fast excitatory synaptic transmission include three types of receptors, which are named for their sensitivity to agonists: N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA), and kainate. Glutamate can also act through metabotropic receptors (i.e., receptors having activation coupled to an intracellular biochemical cascade). Analysis of glutamate receptors by gene expression, immunocytochemistry, and in situ hybridization indicates that primary auditory nerve cells express NMDA (NR1 and NR2A-D), AMPA (GluR2-4), and kainate (GluR5-7) receptor subunits and the high-affinity kainate-binding proteins (KA1 and KA2) (Puel (1995) supra), suggesting that these receptors all coexist on primary auditory nerve cells.
In addition to its fast excitatory properties, glutamate also plays a role in excitotoxicity, a form of neuronal degeneration in the cochlea, which can occur when, for example, glutamate is released in large amounts or when incompletely recycled in the cochlea. Cochlear excitotoxicity plays a role in ischemic- or noise-induced sudden deafness, as well as in tinnitus (Pujol et al. (1999) Ann N Y Acad Sci. 884:249-54; Pujol et al. (1992) NeuroReport 3:299-302; Puel et al. (1994) J. Comp. Neurol. 341:241-256; Puel (1995), supra).
Excitotoxicity can be generally characterized by a two-step mechanism. In the first phase, glutamate causes overactivation of the ionotropic glutamate receptors that are permeable to cations, which leads to excessive ion permeation, osmotic swelling, free radical generation, and neuronal death. The second phase of glutamate excitotoxicity, which may develop after strong and/or repetitive injury, consists of a cascade of metabolic events triggered by the entry of Ca2+, which leads to neuronal death in the spiral ganglion. Neo-synaptogenesis and functional recovery is accompanied by up-regulation of NMDA and metabotropic glutamate receptors.
Prevention of excitotoxicity has been studied using various antagonists of the ionotropic glutamate receptors. Intracochlear perfusion of the glutamate antagonist kynurenate protects against sound-induced synaptic damage in guinea pigs (Puel et al. (1998) NeuroReport 9:2109-2114). Antagonism of the AMPA receptor, e.g., via intracochlear infusion of a selective AMPA receptor antagonist, can block the excitotoxic effect of gultamate in the cochlea. Intracochlear perfusion of 6-7-dinitorquinoxaline-2,3-dione (DNQX) ten minutes prior to or concomitant with AMPA perfusion prevented most of the occurrence of radial dendrite swelling (Puel et al., (1991), supra). Intracochlear perfusion of both DNQX and D-AP5 (a D-2-amino-5-phosphonopentanoate, an NMDA receptor antagonist), provide nearly complete protection of all radial dendrites to AMPA perfusion (Puel et al. (1994) J. Comp Neurol 341:241-256). However, use of intracochlear perfusion methods in the clinic is impractical and, on the whole, unacceptable in humans as it would cause permanent damage to the cochlea. Systemic delivery of compounds that modulate glutamate activity, particularly at dosages sufficient to provide for therapy in the inner ear, cause serious aside-effects, such as memory loss and stupor.
As is evident from the above, there is a great need for devices and methods for effective and practical clinical treatment of inner ear disorders such as hearing loss and related conditions such as tinnitus. The present invention addresses this problem.